Sonic Hedgehog (Shh) Pathway Signaling and Clinical Outcome in Non Small Cell Lung Cancers (NSCLC).
Li Li, Wadad Mneimneh, Christine E Sheehan, Jeffrey S Ross. Albany Medical College, NY
Background: Desert hedgehog (Dhh), patched-1 (PTCH1), smoothened (Smo) and glioma oncogene 1 (Gli-1) proteins are Shh pathway members and that have been implicated in human organogenesis and neoplasia, but have not been widely studied in clinical NSCLC specimens.
Design: FFPE sections from 110 NSCLC, including 31 squamous cell carcinomas (SCC), 41 adenocarcinomas (AC), and 38 bronchoalveolar carcinomas (BAC), were immunostained by automated methods (Ventana) with goat polyclonal Dhh, Smo, and Gli-1 and rabbit polyclonal patched1 antibodies (Santa Cruz Biotech). The staining pattern was semiquantitatively assessed based on staining intensity and distribution and the results were correlated with morphologic and prognostic variables.
Results: Immunoreactivity for Dhh, patched1 and Gli-1 was predominately cytoplasmic, with both nuclear and cytoplasmic noted for Smo. Dhh overexpression was noted in 47% tumors and correlated with tumor type [77% SCC vs 44% AC vs 26% BAC, p<0.0001] and high grade [p=0.036]. Strong diffuse patched overexpression was noted in 46% tumors, correlating overall with tumor type [60% BAC vs 49% AC vs 26% SCC, p=0.019] and early stage [p=0.031]; while within the SCC subgroup only, correlating with high grade [p=0.025], female gender [p=0.031], and disease recurrence [p=0.05]; and within the ACs, correlating with early stage [p=0.047] and lengthened survival [p=0.032]. Strong diffuse Smo overexpression was noted in 58% tumors overall [58% SCC vs 45% BAC vs 39% AC]; with cytoplasmic localization in 30% tumors correlating with lengthened survival [p=0.002] overall and within AC [p=0.013]; and nuclear localization in 20% tumors correlating with tumor type [36% SCC vs 16% BAC vs 11% AC, p=0.027], small tumor size (<= 3.0 cm) [p=0.038], and lack of disease recurrence [p=0.016]. Strong diffuse Gli-1 was overexpressed in 41% tumors overall [50% SCC vs 48% AC vs 25% BAC, p=0.063] and correlated with non-recurrent disease [p=0.028] overall and within AC [p=0.05]. On multivariate analysis advanced stage [p<0.0001], lack of strong diffuse cytoplasmic Smo localization [p=0.005], and loss of nuclear Smo localization [p=0.048] independently predict shortened survival.
Conclusions: Shh pathway proteins are differentially expressed in NSCLC and are associated with NSCLC histologic subtype, tumor stage and variably with clinical outcome. Of the Shh proteins studied, Smo expression loss was the most noteworthy associated with advanced primary tumor stage and independently predicting shortened patient survival.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 255, Tuesday Afternoon